Project Summary. Diabetic retinopathy (DR) is a common complication of diabetes and is the leading cause of blindness in the working population. Currently, >40% of the patient population fails to respond to gold-standard anti-VEGF direct intraocular injection treatments. New therapies that are superior to or synergistic with current approaches are of great value to patients. Unlike current treatment options, new approaches should be non- invasive (into the eye), affordable, and not reliant on specialized facilities. Our research program seeks to develop small molecule PPARα agonists as first-in-class treatments for DR. The promise of PPARα agonism as a novel strategy for treating DR has been confirmed in human clinical trials, wherein Fenofibrate (Feno), a clinically used drug for hyperlipidemia, exhibited robust protective effects against DR and retinal neovascularization (NV) in type 2 diabetic patients. We have determined that the protective effects of Feno are unrelated to its lipid-lowering activity, but rather result from its agonism of PPARα. Feno however, suffers from poor retinal distribution, low affinity/selectivity for PPARα, and chemotype related dose-limiting toxicities, all of which will limit its use as a DR therapy. Recently, we have identified a novel class of non-fibrate PPARα agonists that demonstrate improved potency and selectivity over Feno in vitro and exhibit efficacy in a retinal vascular leakage DR animal model (i.p. administration). All totaled, these data provide proof-of-concept and clearly demonstrate that 1) PPARα maintains critical roles in the major clinical features of DR and 2) Non-fibrate related PPARα agonists with improved physicochemical properties and ocular distribution have high promise to become first-in-class therapeutic options for DR. Specific Aims. (1) Structure-based hit to lead optimization of novel PPARα agonists; (2) Determine the potency and efficacy of newly designed and synthesized analogs; (3) Define the downstream molecular mechanism(s) underlying the protective effects of PPARα agonism against oxidative stress and inflammation in DR. Study Design. We will leverage in silico PPARα models developed in our lab to guide the design of improved agonists. Synthesized analogs will be assessed in in vitro biochemical and cellular assays for PPARα potency, level of agonism, and isoform selectivity. Compounds meeting pre-defined metrics will be advanced to secondary assays to determine anti-angiogenic, anti-oxidative, and neuroprotective effects in vitro. Top compounds will be assessed for efficacy against retinal leukostasis, endothelial impairment, pericyte loss, vascular leakage, visual function, and neuroretinal apoptosis in animal models. Top performing compounds will be utilized for detailed studies to define the downstream molecular mechanisms underlying the protective effects of PPARα agonism against the major etiological drivers of DR. The research is significant in that it will provide new ...